2. Academic Validation
  3. Gut-to-brain signaling restricts dietary protein intake during recovery from catabolic states

Gut-to-brain signaling restricts dietary protein intake during recovery from catabolic states

  • Cell. 2025 Nov 4:S0092-8674(25)01134-1. doi: 10.1016/j.cell.2025.10.005.
Nikolai P Jaschke 1,  Joseph R Luchsinger 2,  Zuojia Chen 3,  Vera C Wulfmeyer 4,  Xavier de la Rosa 4,  Oliver Hahn 4,  Cuiling Zhang 5,  Nathaniel D Bachtel 5,  Jaime L Cullen 5,  Tilman D Rachner 6,  Ruslan Medzhitov 7,  Markus M Rinschen 8,  Chuan Wu 3,  Andrew Wang 9
Affiliations

Affiliations

  • 1 Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Department of Internal Medicine (Rheumatology, Allergy, and Immunology), Yale School of Medicine, New Haven, CT 06510, USA; Department of Medicine I & III, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Hamburg Center for Translational Immunology, Hamburg, Germany. Electronic address: [email protected].
  • 2 Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Department of Psychiatry, Yale School of Medicine, New Haven, CT 06510, USA.
  • 3 Experimental Immunology Branch, National Cancer Institute, NIH, Bethesda, MD, USA.
  • 4 Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • 5 Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA.
  • 6 Department of Medicine III, University Hospital Dresden, Dresden, Germany.
  • 7 Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Tananbaum Center for Theoretical and Analytical Human Biology, Yale University School of Medicine, New Haven, CT, USA.
  • 8 Department of Biomedicine, Aarhus University, Aarhus, Denmark; Department of Medicine III & Hamburg Center for Kidney Health, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • 9 Department of Immunobiology, Yale School of Medicine, New Haven, CT 06510, USA; Department of Internal Medicine (Rheumatology, Allergy, and Immunology), Yale School of Medicine, New Haven, CT 06510, USA. Electronic address: [email protected].
PMID: 41192423 DOI: 10.1016/j.cell.2025.10.005
Abstract

Dietary needs are dynamic, with optimal ranges for nutrients varying over time and across physiological states. How optimal nutrient set points are established and why they are adjusted remains largely unknown. In our efforts to understand the physiology of recovery, we made the surprising observation that mice restrict protein intake at the expense of caloric supply. We identified three amino acids-glutamine (Q), lysine (K), and threonine (T)-within dietary protein, which are necessary and sufficient for protein aversion during recovery from catabolic states. The anorexigenic effects of QKT are driven by ammoniagenesis in the gut, sensed by enterochromaffin cells in a TRPA1-dependent fashion and transduced to brainstem neurons via serotonin signaling, inducing anorexia. We propose that this mechanism serves as a first-line defense against ammonia toxicity. In summary, we identified a set of adaptive food preferences during recovery ("recovery behavior"), with implications for understanding diseases of pathologic recovery and the development of therapeutic interventions deployed to enhance recovery.

Keywords

TRPA1; amino acids; ammonia; dietary protein; gut-brain axis; high protein diet; protein leverage; recovery; urea cycle.

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